Power spectral analysis of heart rate variability has often been used to assess cardiac autonomic function; however, the relationship of low‐frequency (LF) power of heart rate variability to cardiac sympathetic tone has been unclear. With or without adjustment for high‐frequency (HF) power, total power or respiration, LF power seems to provide an index not of cardiac sympathetic tone but of baroreflex function. Manipulations and drugs that change LF power or LF:HF may do so not by affecting cardiac autonomic outflows directly but by affecting modulation of those outflows by baroreflexes.
Brain-derived neurotrophic factor (BDNF) has an important role in regulating maintenance, growth and survival of neurons. However, the main source of circulating BDNF in response to exercise is unknown. To identify whether the brain is a source of BDNF during exercise, eight volunteers rowed for 4 h while simultaneous blood samples were obtained from the radial artery and the internal jugular vein. To further identify putative cerebral region(s) responsible for BDNF release, mouse brains were dissected and analysed for BDNF mRNA expression following treadmill exercise. In humans, a BDNF release from the brain was observed at rest ( P < 0.05), and increased two- to threefold during exercise ( P < 0.05). Both at rest and during exercise, the brain contributed 70â80% of circulating BDNF, while that contribution decreased following 1 h of recovery. In mice, exercise induced a three- to fivefold increase in BDNF mRNA expression in the hippocampus and cortex, peaking 2 h after the termination of exercise. These results suggest that the brain is a major but not the sole contributor to circulating BDNF. Moreover, the importance of the cortex and hippocampus as a source for plasma BDNF becomes even more prominent in response to exercise.
The Journal of Physiology and Experimental Physiology have always used UK legislation as the basis of their policy on ethical standards in experiments on non-human animals. However, for international journals with authors, editors and referees from outside the UK the policy can lack transparency and is sometimes cumbersome, requiring the intervention of a Senior Ethics Reviewer or advice from external experts familiar with UK legislation. The journals have therefore decided to set out detailed guidelines for how authors should report experimental procedures that involve animals. As well as helping authors, this new clarity will facilitate the review process and decision making where there are questions regarding animal ethics.
• What is the topic for this review? During the exercise recovery period, the combination of centrally mediated decreases in sympathetic nerve activity with a reduced signal transduction from sympathetic nerve activation into vasoconstriction, as well as local vasodilator mechanisms, contributes to the fall in arterial blood pressure seen after exercise. • What advances does it highlight? Important findings from recent studies include the recognition that skeletal muscle afferents may play a primary role in postexercise resetting of the baroreflex via discrete receptor changes within the nucleus tractus solitarii and that sustained postexercise vasodilatation of the previously active skeletal muscle is primarily the result of histamine H 1 and H 2 receptor activation. A single bout of aerobic exercise produces a postexercise hypotension associated with a sustained postexercise vasodilatation of the previously exercised muscle. Work over the last few years has determined key pathways for the obligatory components of postexercise hypotension and sustained postexercise vasodilatation and points the way to possible benefits that may result from these robust responses. During the exercise recovery period, the combination of centrally mediated decreases in sympathetic nerve activity with a reduced signal transduction from sympathetic nerve activation into vasoconstriction, as well as local vasodilator mechanisms, contributes to the fall in arterial blood pressure seen after exercise. Important findings from recent studies include the recognition that skeletal muscle afferents may play a primary role in postexercise resetting of the baroreflex via discrete receptor changes within the nucleus tractus solitarii and that sustained postexercise vasodilatation of the previously active skeletal muscle is primarily the result of histamine H 1 and H 2 receptor activation. Future research directions include further exploration of the potential benefits of these changes in the longer term adaptations associated with exercise training, as well as investigation of how the recovery from exercise may provide windows of opportunity for targeted interventions in patients with hypertension and diabetes.
Increased reactive oxygen species (ROS) production is crucial to the remodelling that occurs in skeletal muscle in response to both exercise training and prolonged periods of disuse. This review discusses the redox-sensitive signalling pathways that are responsible for this ROS-induced skeletal muscle adaptation. We begin with a discussion of the sites of ROS production in skeletal muscle fibres. This is followed by an overview of the putative redox-sensitive signalling pathways that promote skeletal muscle adaptation. Specifically, this discussion highlights redox-sensitive kinases, phosphatases and the transcription factor nuclear factor-ÎºB. We also discuss the evidence that connects redox signalling to skeletal muscle adaptation in response to increased muscular activity (i.e. exercise training) and during prolonged periods of muscular inactivity (i.e. immobilization). In an effort to stimulate further research, we conclude with a discussion of unanswered questions about redox signalling in skeletal muscle.
All eukaryotic cells utilize oxidative phosphorylation to maintain their high-energy phosphate stores. Mitochondrial oxygen consumption is required for ATP generation, and cell survival is threatened when cells are deprived of O 2 . Consequently, all cells have the ability to sense O 2 , and to activate adaptive processes that will enhance the likelihood of survival in anticipation that oxygen availability might become limiting. Mitochondria have long been considered a likely site of oxygen sensing, and we propose that the electron transport chain acts as an O 2 sensor by releasing reactive oxygen species (ROS) in response to hypoxia. The ROS released during hypoxia act as signalling agents that trigger diverse functional responses, including activation of gene expression through the stabilization of the transcription factor hypoxia-inducible factor (HIF)-Î±. The primary site of ROS production during hypoxia appears to be complex III. The paradoxical increase in ROS production during hypoxia may be explained by an effect of O 2 within the mitochondrial inner membrane on: (a) the lifetime of the ubisemiquinone radical in complex III; (b) the relative release of mitochondrial ROS towards the matrix compartment versus the intermembrane space; or (c) the ability of O 2 to access the ubisemiquinone radical in complex III. In summary, the process of oxygen sensing is of fundamental importance in biology. An ability to control the oxygen sensing mechanism in cells, potentially using small molecules that do not disrupt oxygen consumption, would open valuable therapeutic avenues that could have a profound impact on a diverse range of diseases.
• What is the topic of this review? The central goal of the research reviewed here is to understand the functional properties of voltage‐gated sodium channels at the level of high‐resolution structure of the channel protein. • What advances does it highlight? The key functional properties of voltage‐gated sodium channels, including voltage‐dependent activation. Sodium conductance and selectivity, block by local anesthetics and related drugs, and both fast and slow inactivation, are now understood at the level of protein structure with high resolution. These emerging high‐resolution structural models may lead to development of safer and more efficacious drugs for treatment of epilepsy, chronic pain, and cardiac arrhythmia through structure‐based drug design. Voltage‐gated sodium channels initiate action potentials in nerve, muscle and other excitable cells. Early physiological studies described sodium selectivity, voltage‐dependent activation and fast inactivation, and developed conceptual models for sodium channel function. This review article follows the topics of my 2013 Sharpey‐Schafer Prize Lecture and gives an overview of research using a combination of biochemical, molecular biological, physiological and structural biological approaches that have elucidated the structure and function of sodium channels at the atomic level. Structural models for voltage‐dependent activation, sodium selectivity and conductance, drug block and both fast and slow inactivation are discussed. A perspective for the future envisions new advances in understanding the structural basis for sodium channel function and the opportunity for structure‐based discovery of novel therapeutics.
New Findings What is the topic of this review? In personalized medicine', various plots and analyses are purported to quantify individual differences in intervention response, identify responders/non-responders and explore response moderators or mediators. What advances does it highlight? We highlight the impact of within-subject random variation, which is inevitable even with gold-standard' measurement tools/protocols and sometimes so substantial that it explains all apparent individual response differences. True individual response differences are quantified only by comparing the SDs of changes between intervention and comparator arms. When these SDs are similar, true individual response differences are clinically unimportant and further analysis unwarranted. Within the hot topic' of personalized medicine, we scrutinize common approaches for presenting and quantifying individual differences in the physiological response to an intervention. First, we explain how popular plots used to present individual differences in response are contaminated by random within-subject variation and the regression to the mean artefact. Using a simulated data set of blood pressure measurements, we show that large individual differences in physiological response can be suggested by some plots and analyses, even when the true magnitude of response is exactly the same in all individuals. Second, we present the appropriate designs and analysis approaches for quantifying the true interindividual variation in physiological response. It is imperative to include a comparator arm/condition (or derive information from a prior relevant repeatability study) to quantify true interindividual differences in response. The most important statistic is the SD of changes in the intervention arm, which should be compared with the same SD in the comparator arm or from a prior repeatability study in the same population conducted over the same duration as the particular intervention. Only if the difference between these SDs is clinically relevant is it logical to go on to explore any moderators or mediators of the intervention effect that might explain the individual response. To date, very few researchers have compared these SDs before making claims about individual differences in physiological response and their importance to personalized medicine.
In the past few years, the classical concept of the renin–angiotensin system (RAS) has experienced substantial conceptual changes. The identification of: the renin/prorenin receptor; the angiotensin‐converting enzyme homologue, ACE2, as an angiotensin peptide‐processing enzyme and a virus receptor for severe acute respiratory syndrome, the Mas as a receptor for angiotensin (1–7) [Ang(1–7)], and the possibility of signaling through ACE have contributed to switch our understanding of the RAS from the classical limited‐proteolysis linear cascade to a cascade with multiple mediators, multiple receptors and multifunctional enzymes. With regard to Ang(1–7), the identification of ACE2 and of Mas as a receptor implicated in its actions contributed to decisively establish this heptapeptide as a biologically active member of the RAS cascade. In this review, we will focus on the recent findings related to the ACE2–Ang(1–7)–Mas axis and, in particular, on its putative role as an ACE–Ang II–AT 1 receptor counter‐regulatory axis within the RAS.
Thermogenesis, the production of heat energy, is an essential component of the homeostatic repertoire to maintain body temperature in mammals and birds during the challenge of low environmental temperature and plays a key role in elevating body temperature during the febrile response to infection. The primary sources of neurally regulated metabolic heat production are mitochondrial oxidation in brown adipose tissue, increases in heart rate and shivering in skeletal muscle. Thermogenesis is regulated in each of these tissues by parallel networks in the central nervous system, which respond to feedforward afferent signals from cutaneous and core body thermoreceptors and to feedback signals from brain thermosensitive neurons to activate the appropriate sympathetic and somatic efferents. This review summarizes the research leading to a model of the feedforward reflex pathway through which environmental cold stimulates thermogenesis and discusses the influence on this thermoregulatory network of the pyrogenic mediator, prostaglandin E 2 , to increase body temperature. The cold thermal afferent circuit from cutaneous thermal receptors ascends via second-order thermosensory neurons in the dorsal horn of the spinal cord to activate neurons in the lateral parabrachial nucleus, which drive GABAergic interneurons in the preoptic area to inhibit warm-sensitive, inhibitory output neurons of the preoptic area. The resulting disinhibition of thermogenesis-promoting neurons in the dorsomedial hypothalamus and possibly of sympathetic and somatic premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, activates excitatory inputs to spinal sympathetic and somatic motor circuits to drive thermogenesis.
New Findings What is the central question of this study? Can physiological concentrations of metabolite combinations evoke sensations of fatigue and pain when injected into skeletal muscle? If so, what sensations are evoked? What is the main finding and its importance? Low concentrations of protons, lactate and ATP evoked sensations related to fatigue. Higher concentrations of these metabolites evoked pain. Single metabolites evoked no sensations. This suggests that the combination of an ASIC receptor and a purinergic P2X receptor is required for signalling fatigue and pain. The results also suggest that two types of sensory neurons encode metabolites; one detects low concentrations of metabolites and signals sensations of fatigue, whereas the other detects higher levels of metabolites and signals ache and hot. The perception of fatigue is common in many disease states; however, the mechanisms of sensory muscle fatigue are not understood. In mice, rats and cats, muscle afferents signal metabolite production in skeletal muscle using a complex of ASIC, P2X and TRPV1 receptors. Endogenous muscle agonists for these receptors are combinations of protons, lactate and ATP. Here we applied physiological concentrations of these agonists to muscle interstitium in human subjects to determine whether this combination could activate sensations and, if so, to determine how the subjects described these sensations. Ten volunteers received infusions (0.2 ml over 30 s) containing protons, lactate and ATP under the fascia of a thumb muscle, abductor pollicis brevis. Infusion of individual metabolites at maximal amounts evoked no fatigue or pain. Metabolite combinations found in resting muscles (pH 7.4 + 300 nm ATP + 1 mm lactate) also evoked no sensation. The infusion of a metabolite combination found in muscle during moderate endurance exercise (pH 7.3 + 400 nm ATP + 5 mm lactate) produced significant fatigue sensations. Infusion of a metabolite combination associated with vigorous exercise (pH 7.2 + 500 nm ATP + 10 mm lactate) produced stronger sensations of fatigue and some ache. Higher levels of metabolites (as found with ischaemic exercise) caused more ache but no additional fatigue sensation. Thus, in a dose-dependent manner, intramuscular infusion of combinations of protons, lactate and ATP leads to fatigue sensation and eventually pain, probably through activation of ASIC, P2X and TRPV1 receptors. This is the first demonstration in humans that metabolites normally produced by exercise act in combination to activate sensory neurons that signal sensations of fatigue and muscle pain.
• What is the topic of this review? This is a personal historical review about the discovery and the main conceptual advances leading to our current understanding of purinergic signalling. The contributions of leading figures in the field are acknowledged. It includes the discovery of purinergic neuromuscular and synaptic transmission, cotransmission, the identification of P1 (adenosine), P2X nucleotide ion channel and P2Y nucleotide G protein‐coupled receptors, the identity of ectonucleotidases and release of ATP from cells by mechanical stimulation and mechanosensory transduction. • What advances does it highlight? It highlights the pathophysiology of purinergic signalling and recent therapeutic developments. This lecture is about the history of the purinergic signalling concept. It begins with reference to the paper by Paton & Vane published in 1963 , which identified non‐cholinergic relaxation in response to vagal nerve stimulation in several species, although they suggested that it might be due to sympathetic adrenergic nerves in the vagal nerve trunk. Using the sucrose gap technique for simultaneous mechanical and electrical recordings in smooth muscle (developed while in Feldberg's department in the National Institute for Medical Research) of the guinea‐pig taenia coli preparation (learned when working in Edith Bülbring's smooth muscle laboratory in Oxford Pharmacology), we showed that the hyperpolarizations recorded in the presence of antagonists to the classical autonomic neurotransmitters, acetylcholine and noradrenaline, were inhibitory junction potentials in response to non‐adrenergic, non‐cholinergic neurotransmission, mediated by intrinsic enteric nerves controlled by vagal and sacral parasympathetic nerves. We then showed that ATP satisfied the criteria needed to identify a neurotransmitter released by these nerves. Subsequently, it was shown that ATP is a cotransmitter in all nerves in the peripheral and central nervous systems. The receptors for purines and pyrimidines were cloned and characterized in the early 1990s, and immunostaining showed that most non‐neuronal cells as well as nerve cells expressed these receptors. The physiology and pathophysiology of purinergic signalling is discussed. Professor Geoffrey Burnstock, President of the Autonomic Neuroscience Centre, University College Medical School, London, UK
Converging lines of evidence from epidemiological studies and animal models now indicate that the origins of obesity and related metabolic disorders lie not only in the interaction between genes and traditional adult risk factors, such as unbalanced diet and physical inactivity, but also in the interplay between genes and the embryonic, fetal and early postnatal environment. Whilst studies in man initially focused on the relationship between low birth weight and risk of adult obesity and metabolic syndrome, evidence is also growing to suggest that increased birth weight and/or adiposity at birth can also lead to increased risk for childhood and adult obesity. Hence, there appears to be increased risk of obesity at both ends of the birth weight spectrum. Animal models, including both under- and overnutrition in pregnancy and lactation lend increasing support to the developmental origins of obesity. This review focuses upon the influence of the maternal nutritional and hormonal environment in pregnancy in permanently programming appetite and energy expenditure and the hormonal, neuronal and autocrine mechanisms that contribute to the maintenance of energy balance in the offspring. We discuss the potential maternal programming âvectorsâ and the molecular mechanisms that may lead to persistent pathophysiological changes resulting in subsequent disease. The perinatal environment, which appears to programme subsequent obesity, provides a potential therapeutic target, and work in this field will readily translate into improved interventional strategies to stem the growing epidemic of obesity, a disease which, once manifest, has proven particularly resistant to treatment.
New Findings What is the topic of this review? Over the past decade, our team has investigated interindividual variability in human blood pressure regulation. What advances does it highlight? In men, we have found a tight relationship between indices of sympathetic activity and vascular resistance across the age span. This relationship is absent in young women but seen in postmenopausal women. These sex and age differences in vascular resistance are largely a result of changes in the balance of vasodilating and vasoconstricting adrenergic receptor tone. When these changes are considered along with cardiac output, a coherent picture is beginning to emerge of why blood pressure rises more with age in women than men. Arterial pressure is a key regulated variable in the cardiovascular system with important health implications. Over the last 12years, we have used physiological measurements, including muscle sympathetic nerve activity (MSNA), to explore the balance among mean arterial blood pressure, cardiac output and total peripheral resistance (TPR) in normotensive humans. We have shown that these determinants of blood pressure can vary widely in different subjects and how they vary depends on sex and age. In young men, there is a direct relationship between MSNA and TPR but no relationship with blood pressure. This is because cardiac output is proportionally lower in those with high MSNA and TPR. In contrast, in young women there is no relationship between MSNA and TPR (or cardiac output); this is because -adrenergic vasodilator mechanisms offset -adrenergic vasoconstriction. Thus, blood pressure is unrelated to MSNA in young women. In older women, -adrenergic vasodilator mechanisms are diminished, and a direct relationship between MSNA and TPR is seen. In older men, the relationships among these variables are less clear cut, perhaps owing to age-related alterations in endothelial function. With ageing, the relationship between MSNA and blood pressure becomes positive, more so in women than in men. The finding that the physiological control of blood pressure is so different in men and women and that it varies with age suggests that future studies of mechanisms of hypertension will reveal corresponding differences among groups.
• What is the central question of this study? Ischaemia–reperfusion of peripheral tissues protects the heart from subsequent myocardial ischaemia–reperfusion‐induced injury and cardiac dysfunction, a phenomenon referred to as ‘remote ischaemic preconditioning’ (rIPC). This study addressed whether activation of sensory afferent nerves in the ischaemic hindlimb and vagal efferent nerves innervating the heart mediate rIPC. • What is the main finding and its importance? Spinal cord section, bilateral vagotomy or blockade of muscarinic cholinergic receptors in vivo abolished rIPC and cardioprotection measured in vitro . Electrical stimulation of the vagus nerve induced cardioprotection, thus mimicking rIPC. The finding that sensory and parasympathetic neural mechanisms mediate rIPC confirms and extends previous results, with implications for translational studies in patients with coronary artery disease. This investigation was designed to determine the participation of the vagus nerve and muscarinic receptors in the remote ischaemic preconditioning (rIPC) mechanism. New Zealand rabbits were anaesthetized, and the femoral artery was dissected. After 30 min of monitoring, the hearts were isolated and subjected to 30 min of global no‐flow ischaemia and 180 min of reperfusion (non‐rIPC group). The ventricular function was evaluated, considering the left ventricular developed pressure and the left ventricular end‐diastolic pressure. In the rIPC group, the rabbits were subjected to three cycles of hindlimb ischaemia (5 min) and reperfusion (5 min), and the same protocol as that used in non‐rIPC group was then repeated. In order to evaluate the afferent neural pathway during the rIPC protocol we used two groups, one in which the femoral and sciatic nerves were sectioned and the other in which the spinal cord was sectioned (T9–T10 level). To study the efferent neural pathway during the rIPC protocol, the vagus nerve was sectioned and, in another group, atropine was administered. The effect of vagal stimulation was also evaluated. An infarct size of 40.8 ± 3.1% was obtained in the non‐rIPC group, whereas in rIPC group the infarct size decreased to 16.4 ± 3.5% ( P < 0.05). During the preconditioning protocol, the vagus nerve section and the atropine administration each abolished the effect of rIPC on infarct size. Vagal stimulation mimicked the effect of rIPC, decreasing infarct size to 15.2 ± 4.7% ( P < 0.05). Decreases in infarct size were accompanied by improved left ventricular function. We demonstrated the presence of a neural afferent pathway, because the spinal cord section completely abolished the effect of rIPC on infarct size. In conclusion, rIPC activates a neural afferent pathway, the cardioprotective signal reaches the heart through the vagus nerve (efferent pathway), and acetylcholine activates the ischaemic preconditioning phenomenon when acting on the muscarinic receptors.
New Findings What is the central question of this study? The prevalence of sedentary behaviour in the workplace and increased daily sitting time have been associated with the development of cardiovascular disease; however, studies investigating the impact of sitting on vascular function remain limited. What is the main finding and its importance? Wedemonstrate that there isa marked vulnerability of the vasculature in the lower and upper limbs to prolonged sitting and highlight the importance of physical activity in restoringvascular function in a limb-specific manner. Sedentary behaviour in the workplace and increased daily sitting time are on the rise; however, studies investigating the impact of sitting on vascular function remain limited. Herein, we hypothesized that 6h of uninterrupted sitting would impair limb micro- and macrovascular dilator function and that this impairment could be improved with a bout of walking. Resting blood flow, reactive hyperaemia to 5min cuff occlusion (microvascular reactivity) and associated flow-mediated dilatation (FMD; macrovascular reactivity) were assessed in popliteal and brachial arteries of young men at baseline (Pre Sit) and after 6h of uninterrupted sitting (Post Sit). Measures were then repeated after a 10min walk (approximate to 1000steps). Sitting resulted in a marked reduction of resting popliteal artery mean blood flow and mean shear rate (6h mean shear rate, -52 +/- 8s(-1)versus Pre Sit, P<0.05). Interestingly, reductions were also found in the brachial artery (6h mean shear rate, -169 +/- 41s(-1)versus Pre Sit, P<0.05). Likewise, after 6h of sitting, cuff-induced reactive hyperaemia was reduced in both the lower leg (-43 +/- 7% versus Pre Sit, P<0.05) and forearm (-31 +/- 11% versus Pre Sit, P<0.05). In contrast, popliteal but not brachial artery FMD was blunted with sitting. Notably, lower leg reactive hyperaemia and FMD were restored after walking. Collectively, these data suggest that prolonged sitting markedly reduces lower leg micro- and macrovascular dilator function, but these impairments can be fully normalized with a short bout of walking. In contrast, upper arm microvascular reactivity is selectively impaired with prolonged sitting, and walking does not influence this effect.
• What is the central question of this study? Heart failure is associated with persistent sterile inflammation that worsens disease severity; however, the molecular mechanisms behind cytokine recruitment and their relevance in the diseased myocardium remain unknown. • What is the main finding and its importance? We show that interleukin‐1β is activated downstream of the Nlrp3 inflammasome in calcineurin‐transgene‐induced structural heart disease. Genetic deletion of Nlrp3 abrogated inflammasome signalling and interleukin‐1β release, improving function. The role of Nlrp3 in non‐ischaemic cardiomyopathy and the utility of inflammasome antagonism have not yet been explored, revealing potential for translational application. Heart failure is associated with a low‐grade and chronic cardiac inflammation that impairs function; however, the mechanisms by which this sterile inflammation occurs in structural heart disease remain poorly defined. Cardiac‐specific heterozygous overexpression of the calcineurin transgene (CNTg) in mice results in cardiac hypertrophy, inflammation, apoptosis and ventricular dilatation. We hypothesized that activation of the Nlrp3 inflammasome, an intracellular danger‐sensing pathway required for processing the pro‐inflammatory cytokine interleukin‐1β (IL‐1β), may contribute to myocardial dysfunction and disease progression. Here we report that Nlrp3 mRNA was increased in CNTg mice compared with wild‐type. Consistent with inflammasome activation, CNTg animals had increased conversion of pro‐caspase‐1 to cleaved and activated forms, as well as markedly increased serum IL‐1β. Blockade of IL‐1β signalling via chronic IL‐1 receptor antagonist therapy reduced cardiac inflammation and myocyte pathology in CNTg mice, resulting in improved systolic performance. Furthermore, genetic ablation of Nlrp3 in CNTg mice reduced pro‐inflammatory cytokine maturation and cardiac inflammation, as well as improving systolic performance. These findings indicate that activation of the Nlrp3 inflammasome in CNTg mice promotes myocardial inflammation and systolic dysfunction through the production of pro‐inflammatory IL‐1β. Blockade of IL‐1β signalling with the IL‐1 receptor antagonist reverses these phenotypes and offers a possible therapeutic approach in the management of heart failure.
The ‘inflammatory reflex’ acts through efferent neural connections from the central nervous system to lymphoid organs, particularly the spleen, that suppress the production of inflammatory cytokines. Stimulation of the efferent vagus has been shown to suppress inflammation in a manner dependent on the spleen and splenic nerves. The vagus does not innervate the spleen, so a synaptic connection from vagal preganglionic neurons to splenic sympathetic postganglionic neurons was suggested. We tested this idea in rats. In a preparatory operation, the anterograde tracer DiI was injected bilaterally into the dorsal motor nucleus of vagus and the retrograde tracer Fast Blue was injected into the spleen. On histological analysis 7–9 weeks later, 883 neurons were retrogradely labelled from the spleen with Fast Blue as follows: 89% in the suprarenal ganglia (65% left, 24% right); 11% in the left coeliac ganglion; but none in the right coeliac or either of the superior mesenteric ganglia. Vagal terminals anterogradely labelled with DiI were common in the coeliac but sparse in the suprarenal ganglia, and confocal analysis revealed no putative synaptic connection with any Fast Blue‐labelled cell in either ganglion. Electrophysiological experiments in anaesthetized rats revealed no effect of vagal efferent stimulation on splenic nerve activity or on that of 15 single splenic‐projecting neurons recorded in the suprarenal ganglion. Together, these findings indicate that vagal efferent neurons in the rat neither synapse with splenic sympathetic neurons nor drive their ongoing activity.
Activation of angiotensin‐converting enzyme 2 (ACE2), production of angiotensin‐(1–7) [Ang‐(1–7)] and stimulation of the Ang‐(1–7) receptor Mas exert beneficial actions in various peripheral cardiovascular diseases, largely through opposition of the deleterious effects of angiotensin II via its type 1 receptor. Here we considered the possibility that Ang‐(1–7) may exert beneficial effects against CNS damage and neurological deficits produced by cerebral ischaemic stroke. We determined the effects of central administration of Ang‐(1–7) or pharmacological activation of ACE2 on the cerebral damage and behavioural deficits elicited by endothelin‐1 (ET‐1)‐induced middle cerebral artery occlusion (MCAO), a model of cerebral ischaemia. The results of the present study demonstrated that intracerebroventricular infusion of either Ang‐(1–7) or an ACE2 activator, diminazine aceturate (DIZE), prior to and following ET‐1‐induced MCAO significantly attenuated the cerebral infarct size and neurological deficits measured 72 h after the insult. These beneficial actions of Ang‐(1–7) and DIZE were reversed by co‐intracerebroventricular administration of the Mas receptor inhibitor, A‐779. Neither the Ang‐(1–7) nor the DIZE treatments altered the reduction in cerebral blood flow elicited by ET‐1. Lastly, intracerebroventricular administration of Ang‐(1–7) significantly reduced the increase in inducible nitric oxide synthase mRNA expression within the cerebral infarct that occurs following ET‐1‐induced MCAO. This is the first demonstration of cerebroprotective properties of the ACE2–Ang‐(1–7)–Mas axis during ischaemic stroke, and suggests that the mechanism of the Ang‐(1–7) protective action includes blunting of inducible nitric oxide synthase expression.
Beneficial effects of exercise training on the vasculature have been consistently reported in subjects with cardiovascular risk factors or disease, whereas studies in apparently healthy subjects have been less uniform. In this review, we examine evidence pertaining to the impact of exercise training on conduit and resistance vessel function and structure in asymptomatic subjects. Studies of arterial function in vivo have mainly focused on the endothelial nitric oxide dilator system, which has generally been shown to improve following training. Some evidence suggests that the magnitude of benefit depends upon the intensity or volume of training and the relative impact of exercise on upregulation of dilator pathways versus effects of inflammation and/or oxidation. Favourable effects of training on autonomic balance, baroreflex function and brainstem modulation of sympathetic control have been reported, but there is also evidence that basal vasoconstrictor tone increases as a result of training such that improvements in intrinsic vasodilator function and arterial remodelling are counterbalanced at rest. Studies of compliance suggest increases in both the arterial and the venous sides of the circulation, particularly in older subjects. In terms of mechanisms, shear stress appears to be a key signal to improvement in vascular function, whilst increases in pulse pressure and associated haemodynamics during bouts of exercise may transduce vascular adaptation, even in vascular beds which are distant from the active muscle. Different exercise modalities are associated with idiosyncratic patterns of blood flow and shear stress, and this may have some impact on the magnitude of exercise training effects on arterial function and remodelling. Other studies support the theory that that there may be different time course effects of training on specific vasodilator and constrictor pathways. A new era of understanding of the direct impacts of exercise and training on the vasculature is evolving, and future studies will benefit greatly from technological advances which allow direct characterization of arterial function and structure.